Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Interdisciplinary fetal neurology care: Current practice, challenges, and future directions.

As the field of fetal-neonatal neurology has expanded over the past 2 decades with increasingly complex diagnoses, multidisciplinary collaboration with many subspecialties including genetics, neonatology, obstetrics, maternal fetal medicine, surgical sub-specialties, cardiology, radiology, palliative care, and ethics has needed to evolve to strive to offer optimal patient care. While comprehensive care delivery with an inter-disciplinary approach is preferred, there are often barriers based on numerous health disparities especially in resource limited settings. Even in the context of comprehensive care, diagnostic and prognostic uncertainty lead to challenges for providers during fetal neurology consultations. We present a case that highlights advantages of a comprehensive multi-disciplinary team in caring for the medical and social challenges of patients faced with a fetal neurologic diagnosis. Inter-disciplinary training focusing on maternal, fetal, neonatal, and childhood neurodevelopmental course and collaboration among the numerous stakeholders that contribute to fetal neurology practice is needed to provide optimal counseling and care for families faced with a fetal neurological diagnosis.

Recognition and Management of Delirium in the Neonatal Intensive Care Unit: Case Series From a Single-Center Level IV Intensive Care Unit.

Delirium often goes unrecognized in neonates and children because of lack of experience in evaluating behavior and cognition, insufficient awareness of the prevalence, and nondistinctive symptoms in this population. Although there are increasing reports of the presence of delirium in neonates, there are little data to guide the pharmacologic treatment in this population. In this retrospective single-center case series, we present our experience using quetiapine to treat delirium in 9 medically complex neonates. Based on an extensive literature review, expert opinion, and institutional experience, we propose an approach for monitoring and treating delirium in neonates and infants.

Characteristic Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.

Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.

Advancing the Field of Fetal Neurology: A Call for Global Collaborations.

Fetal Neurology continues to grow as a distinct subspecialty informed by evolving precision diagnosis with advancements in prenatal neuroimaging, genetic and infectious testing. While there are inherent limitations and challenges in prenatal diagnostic testing and prognostic counseling, the interdisciplinary approach allows comprehensive guidance for perinatal and postnatal management of neurological disorders detected early in development. The current practice of fetal neurology is heterogenous and variable across centers. In low- and middle-income countries (LMICs), fetal neurology practice is under the umbrella of neonatal and perinatal medicine. Since infrastructure and capacity for prenatal diagnostic and prognostic counseling may be variable, the practice approach may have to be modified regionally based on resources, education, and setting. There is a need for collaborative development of educational opportunities, training, guidelines, and research exploring short- and long-term outcome of prenatally identified neurological conditions. Interdisciplinary collaborations and global professional networks are crucial to advance this unique subspecialty.

Fetal Neurology Practice Survey: Current Practice and the Future Directions.

BACKGROUND: Fetal neurology is a rapidly evolving field. Consultations aim to diagnose, prognosticate, and coordinate prenatal and perinatal management along with other specialists and counsel expectant parents. Practice parameters and guidelines are limited. METHODS: A 48-question online survey was administered to child neurologists. Questions targeted current care practices and perceived priorities for the field. RESULTS: Representatives from 43 institutions in the United States responded; 83% had prenatal diagnosis centers, and the majority performed on-site neuroimaging. The earliest gestational age for fetal magnetic resonance imaging was variable. Annual consultations ranged from <20 to >100 patients. Fewer than half (n = 17.40%) were subspecialty trained. Most respondents (n = 39.91%) were interested in participating in a collaborative registry and educational initiatives. CONCLUSIONS: The survey highlights heterogeneity in clinical practice. Large multisite and multidisciplinary collaborations are essential to gather data that inform outcomes for fetuses evaluated across institutions through registries as well as creation of guidelines and educational material.

Role of palliative care in fetal neurological consultations: Guiding through uncertainty and hope.

Fetal neurology is a rapidly evolving and expanding field. Discussions about diagnosis, prognosis, treatment options, and goals of care often begin in the antenatal period. However, there are inherent challenges to fetal counseling of neurological diagnoses due to limitations of fetal imaging, prognostic uncertainty, and variability in neurodevelopmental outcomes. In the midst of uncertainty, families are challenged with preparing a care plan for their baby while simultaneously experiencing profound grief. The paradigms of perinatal palliative care can assist with the grieving process and help frame diagnostic testing and complex decision-making within the context of a family's spiritual, cultural, and social belief system. This ultimately leads to a shared decision-making process and value driven medical care. While perinatal palliative care programs have expanded, many families faced with such diagnoses never meet with a palliative care team prior to delivery. Moreover, there is significant variability in the availability of palliative care services throughout the country. Using an illustrative vignette of a patient with a prenatally diagnosed encephalocele, this review aims to provide a basic framework of perinatal palliative care for fetal neurology diagnoses that emphasizes 1) importance of clear, consistent, and transparent communication among all subspecialists and families, 2) creation of a palliative care birth plan, 3) importance of consistent care providers and longitudinal points of contact prenatally and post-delivery, 4) close communication between the prenatal and post-natal providers to allow for optimal continuity of care, and 5) recognize that information, care plans, and goals of care often evolve over time.

Muslim perspectives on palliative care in perinatal and neonatal patients: a mini-review.

Muslims comprise nearly a quarter of the worldwide population, with significant populations in the United States, Canada, and Europe. As clinicians, it is important to be familiar with Islamic religious and cultural perspectives on medical treatment, life-prolonging measures and comfort and palliative care, but historically, this has been a gap in the literature. Recently, there have been multiple papers discussing Islamic bioethics, particularly in regards to end of life care in adults; however, there has been a lack of literature discussing the Islamic perspective on issues related to neonatal and perinatal end of life care. This paper uses clinical scenarios to review key relevant principles of Islamic law, discussing the primary and secondary sources used in formulating fatawa, including the Quran, hadith, qiyas, and 'urf, and the importance of preservation of life and upholding of human dignity (karamah). Neonatal and perinatal scenarios are used to specifically explore the Islamic perspective on withholding and withdrawal of life-sustaining measures and determining what constitutes an acceptable quality of life. In some Islamic cultures the expertise of the patient's physician is given significant weight in making these judgments, and as such, families may appreciate frank assessment of the situation by the clinical team. Because of the various factors involved in issuing religious ruling, or fatwa, there is a wide spectrum of opinions on these rulings, and physicians should be aware of these differences, seek counsel and guidance from local Islamic leaders, and support families in their decision-making process.

Prenatal Neurological Diagnosis: Challenges in Neuroimaging, Prognostic Counseling, and Prediction of Neurodevelopmental Outcomes.

Prenatal diagnosis of fetal brain abnormalities is rapidly evolving with the advancement of neuroimaging techniques, thus adding value to prognostic counseling and perinatal management. However, challenges and uncertainties persist in prenatal counseling due to limitations of prenatal imaging, continued development and maturation of the brain structure, and the heterogeneity and paucity of outcome studies. This topical review of fetal neurological consultations highlights prenatally diagnosed brain abnormalities that challenged prognostic counseling and perinatal management. Representative cases across multiple centers that highlighted diagnostic challenges were selected. Charts were reviewed for neuroimaging, genetic evaluation, prenatal prognostic discussion, postnatal imaging and testing, and infant outcome. We present case studies with prenatal and postnatal information discussing prenatal testing, fetal MRI interpretation, and complexities in the prognostic counseling process. Advocating for large-scale multicenter studies and a national collaborative fetal neurological registry to help guide the ever-expanding world of prenatal diagnostics and prognostic counseling is critical to this field. Study of large-scale outcomes data from such a registry can better guide fetal neurological consultations and facilitate comprehensive multidisciplinary planning and program development for educational curriculum for fetal-neonatal neurology.

Imaging Similarities Between Oral-Facial-Digital Syndrome Type 1 and Aicardi Syndrome: Prenatal and Postnatal Magnetic Resonance Imaging (MRI) Findings in 4 Patients.

Prenatal identification by magnetic resonance imaging (MRI) of callosal anomalies, particularly with accompanying intracranial abnormalities, poses a challenge for accurate prognostication and fetal counseling as outcome can vary widely depending on underlying etiology. In female patients, Aicardi syndrome is an important consideration, and prompt postnatal ophthalmologic assessment to identify ocular stigmata of Aicardi syndrome can aid with anticipatory guidance and greater vigilance for seizures. We present a case of a female with fetal and postnatal MRI findings of agenesis of corpus callosum and type 2b interhemispheric cysts, characteristically found in Aicardi syndrome, but was found to have oral-facial-digital syndrome type 1 (OFD1). We also present 3 other companion cases with pre- and postnatal imaging of patients with Aicardi syndrome. These cases highlight the importance of widening the differential diagnosis to also include OFD1 for female patients with callosal anomalies.

Value of pre- and postnatal magnetic resonance imaging in the evaluation of congenital central nervous system anomalies.

Fetal MRI and neonatal MRI of the central nervous system (CNS) are complementary tools that can help to accurately counsel and direct the management of children with anomalies of the central nervous system. Postnatal MRI can add to fetal MRI by allowing for monitoring of changes in the severity of disease, better delineation of a suspected prenatal anomaly, evaluation for secondary pathologies related to the primary diagnosis, and surgical management direction. In this review we discuss the roles of fetal and neonatal MRI in the diagnosis and treatment of congenital anomalies of the CNS through a series of case examples and how both are important in patient management.

Short- and Long-Term Outcomes of Prenatally Diagnosed Dandy-Walker Malformation, Vermian Hypoplasia, and Blake Pouch Cyst.

Dandy-Walker continuum, which includes Dandy-Walker malformation, vermian hypoplasia, and Blake pouch cyst, is among the most commonly diagnosed posterior fossa malformation by fetal magnetic resonance imaging (MRI). The objective of our retrospective study was to evaluate fetal and postnatal MRI scan and clinical outcomes. Seventy-two patients were identified; 40 patients had postnatal imaging and follow-up (7 Dandy-Walker malformation, 26 vermian hypoplasia, and 7 Blake pouch cyst). Although all patients with Dandy-Walker malformation required ventriculoperitoneal shunts and 66% were intubated at birth, none required tracheostomy tube and 2 of 5 surviving children had no neurologic deficits. Vermian hypoplasia was strongly associated with genetic conditions and cardiac malformations; odds of not ambulating normally were 12 times greater if a syndrome or injury was present. Echocardiogram and genetic screening are recommended with vermian hypoplasia. There is a risk for epilepsy in both Dandy-Walker malformation and vermian hypoplasia. Blake pouch cyst can be complicated by hydrocephalus, but outcome is favorable.

Fetal Magnetic Resonance Imaging (MRI) in Holoprosencephaly and Associations With Clinical Outcome: Implications for Fetal Counseling.

Holoprosencephaly is the most common malformation of forebrain development and includes a wide spectrum of severity. The objective of this retrospective study was to evaluate fetal magnetic resonance imaging (MRI) associations with outcome. Of the 63 cases identified on antenatal ultrasonography, 28 cases were confirmed on fetal MRI. There were 17 live births; 9 patients died within the first month of life. There were 7 survivors. The vast majority were nonambulatory and required feeding support; none required respiratory support. We found that presence and number of non-holoprosencephaly-associated malformations was also associated with survival. Of 5 patients with 3 or more systemic anomalies, 4 died regardless of holoprosencephaly subtype and 1 was lost to follow-up. Patients with suspected holoprosencephaly on ultrasonography should have full body fetal MRI and echocardiogram to better evaluate systemic anomalies. Counseling should involve pediatric palliative care services to prepare families in caring for babies with limited life span.

Fetal and postnatal MRI findings of Blake pouch remnant causing obstructive hydrocephalus.

Blake pouch remnant, also known as Blake pouch cyst or persistent Blake pouch, is a posterior fossa embryologic anomaly that is often seen in isolation with most affected patients being asymptomatic. However, even in isolation, Blake pouch remnant can result in obstructive hydrocephalus requiring early neurosurgical intervention making it an important diagnosis for the fetal radiologist to consider. We present a rare case of a patient with prenatally diagnosed "inferior vermian hypoplasia" on fetal MRI that went on to develop progressive obstructive hydrocephalus in infancy secondary to what was determined to be a Blake pouch remnant.

Prenatal evaluation of the Sakoda complex.

Sakoda complex is a rare but distinct combination of birth defects consisting of a basal cephalocele, agenesis of the corpus callosum, and midline cleft lip/palate. It has been reported in association with ophthalmologic abnormalities, cognitive deficits and severe epilepsy. Here we describe both prenatal and postnatal MRI findings of a classic case of Sakoda complex in a child with characteristic findings on fetal MRI; prenatal findings have not been described in the literature. Diagnosis of this entity has important implications for prenatal counseling and perinatal management, as is demonstrated in this case.

Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features.

Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.

Fetal brain MRI findings and neonatal outcome of common diagnosis at a tertiary care center.

Fetal Magnetic Resonance Imaging (MRI) is increasingly used in prenatal evaluations. OBJECTIVE: Identify common brain malformations on fetal MRI and evaluate perinatal course. METHODS: Fetal consultations from 10/2016 to 12/2017 reviewed. RESULTS: Hundred consultations were requested; 94 were completed. Findings included: posterior fossa malformations (19%), agenesis/dysgenesis of corpus callosum (15%), congenital aqueductal stenosis (CAS) (14%), ventriculomegaly (11%), isolated cortical malformations (8.5%), and holoprosencephaly (6%). Posterior fossa malformations were more likely to be associated with genetic conditions and cardiac malformations. Patients with CAS all required intensive care unit admission. Overall, few patients with congenital brain malformations required feeding or respiratory support at discharge. None had seizures as neonates except two with early epileptic encephalopathy syndromes. CONCLUSIONS: Even though long term neurological prognosis is poor for many conditions including high lifetime risk of epilepsy, most are discharged with no feeding or respiratory support. Seizures are rarely seen in the neonatal period.

White Matter Lesions Detected by Magnetic Resonance Imaging in Neonates and Children With Congenital Myotonic Dystrophy.

BACKGROUND: Congenital myotonic dystrophy (CDM1) is an autosomal dominant genetic disorder caused by abnormal cytosine-thymine-guanine trinucleotide repeat expansion that results in weakness and cognitive deficits. Studies detailing brain magnetic resonance imaging (MRI) findings in neonates and children with this condition are limited. OBJECTIVE: We evaluated the brain MRI findings in children, including neonates with CDM1, to assess the nature of central nervous system involvement and progression of MRI lesions over time. METHODS: The Cincinnati Children's Hospital neuromuscular disease database was used to identify 16 patients with CDM1 with genetically proven CDM1 who had undergone brain MRI. Hospital charts were reviewed to collect clinical information. RESULTS: Ninety-four percent of patients had an abnormal MRI showing injury to the white matter. Nine patients underwent imaging before eight days of life, and eight of these patients showed signs of injury to the white matter. Three neonates had follow-up MRI scans, and all showed progression of injury. Seven patients had the first MRI between age 29 days and 22 years, and all had abnormalities involving the white matter. Two patients had additional congenital brain malformations, and one patient also harbored a mutation in CDKL5 with resultant epilepsy. CONCLUSIONS: White matter abnormalities are found in patients with CDM1, even in the neonatal period. Many patients present with hypoxia and receive a diagnosis of hypoxic-ischemic encephalopathy and may even undergo therapeutic hypothermia. If MRI findings of white matter injury do not correlate with hypotonia and weakness, further evaluation for CDM1 should be considered.

Clinical, Neuroimaging, and Electrographic Predictors of Phenobarbital Failure in Newborns With Hypoxic Ischemic Encephalopathy and Seizures.

BACKGROUND: Many neonates with hypoxic ischemic encephalopathy and seizures do not respond to the first line antiepileptic drug, phenobarbital. Little is known about what factors are associated with its failure. OBJECTIVE: To examine factors associated with failure of phenobarbital therapy in neonates with hypoxic ischemic encephalopathy and seizures. DESIGN/METHODS: A single-center retrospective review of 50 term (>35 weeks) neonates with hypoxic ischemic encephalopathy and seizures treated with phenobarbital as the first-line antiepileptic. Neonates were classified into either responders (n = 30) or nonresponders (n = 20). Nonresponse was defined as continued seizures after maximum dosing of phenobarbital or an additional antiepileptic. Subjects with acceptable magnetic resonance imaging (MRI) scans obtained within 2 weeks of birth were included in the study and rated using an MRI injury scoring system. Charts were reviewed for demographic, clinical, and laboratory variables. Resuscitation and seizure scores were also calculated. Electroencephalographic (EEG) background activity was reviewed in 2 different time epochs (12-24 hours and 24-36 hours of life) and graded as per ACNS guidelines. RESULTS: There were no significant group differences in demographic, clinical, and laboratory variables except nonresponders, who had higher mean seizure score (P = .01) and significantly more injury on MRI scan for white matter (P = .004), parenchymal cortex (P = .027), and watershed (P = .009) regions. Neonates with moderately abnormal or severely abnormal background EEG responded poorly to phenobarbital. CONCLUSION: In the presence of above factors, one can anticipate that additional antiepileptic medication may be needed. These data also support that larger studies should be done to look prospectively at using alternative agents first line in patients with severe injury.

Outcome of Isolated Absent Septum Pellucidum Diagnosed by Fetal Magnetic Resonance Imaging (MRI) Scan.

Improved fetal imaging has resulted in increased diagnosis of isolated absent septum pellucidum without other intracranial abnormalities. There is little literature regarding outcomes for these fetuses. This study hypothesized the majority of infants diagnosed by fetal magnetic resonance imaging (MRI) with isolated absent septum pellucidum would retain this diagnosis postnatally. Specifically, in the absence of postnatal endocrine or ophthalmologic abnormalities, postnatal imaging would find no additional related findings, and fetuses would be at low risk for developmental delay. Two of 8 subjects met postnatal criteria for septo-optic dysplasia; remaining subjects had normal postnatal endocrine and ophthalmologic evaluations and no significant related findings on postnatal MRI. One subject without septo-optic dysplasia had delays on developmental screening; all others had normal screening (range of follow-up 8-72 months). Our study questions the necessity of postnatal imaging for prenatally diagnosed isolated absent septum pellucidum. Majority of fetuses with isolated absent septum pellucidum retained this diagnosis postnatally.